Many of the detrimental metabolic consequences of obesity are closely related to a central or intraabdominal (IA) distribution of fat. Aging is associated with increased "fatness', increased central/IA adiposity and frequent metabolic abnormalities similar to those observed in younger obese patients. The regulation of fat cell size in specific fat depots and thus the distribution of adiposity in the elderly has not been previously investigated. Of the important regulators of fat cell size, the sympathetic nervous system (SNS) activity, may play the most critical role. There is strong evidence that differential adrenergic responsiveness (beta vs alpha2) in specific fat depots plays an important role in the regulation of fat cell lipolysis. Furthermore, there is some in vitro evidence that adipose tissue lipoprotein lipase (AT-LPL), the rate limiting enzyme for triglyceride (TG) storage, is also regulated by adrenergic mechanisms in a manner inverse to lipolysis. Both young obese and elderly subjects appear to have a chronic increase in SNS activity. We hypothesize that this chronic increase in adrenergic tone produces a desensitization of beta, but not alpha2, adrenergic mechanisms in fat cells. The fat cells in which this change would produce the greatest impact are those with the highest beta responsiveness under normal conditions (Central/IA depots, see Appendix, Fig 1). Beta adrenergic desensitization would reduce hormone sensitive lipase (HSL) mediated lipolysis and possibly increase AT-LPL mediated TG storage (see Appendix, Fig 2) preferentially in these normally very beta responsive central/IA depots, thus promoting an accumulation of fat. We hypothesize that with weight loss the associated decline in SNS activity will reverse the beta adrenergic desensitization and cause a preferential loss of central/IA adiposity. In this proposal we will prospectively study central (abdominal) and peripheral (gluteal) fat depots in obese elderly subjects before and after dietary weight loss in order to attempt to elucidate the mechanisms by which increased SNS activity may regulate fat distribution. We will measure: 1) SNS activity as reflected by both arterialized plasma catecholamine concentrations and nonepinephrine (NE) kinetics; 2) fat cell (and peripheral blood cell) beta and alpha2 adrenergic receptor concentrations and activity (including adenylate cyclase activity); 3) adrenergically stimulated fat cell lipolytic rates; 4) AT-LPL activity,mass and messenger RNA (m-RNA); 5) fat cell size on frozen section; 6) insulin sensitivity using the Bergman minimal model; and 7) lipoprotein profiles.